AU2018241298B2

AU2018241298B2 - Method for the synthesis of 9,10-bis(chloromethyl)anthracene

Info

Publication number: AU2018241298B2
Application number: AU2018241298A
Authority: AU
Inventors: Fernando LANGA DE LA PUENTE; Francisco José ORTEGA HIGUERUELO
Original assignee: Universidad de Castilla La Mancha
Current assignee: Universidad de Castilla La Mancha
Priority date: 2017-03-29
Filing date: 2018-03-16
Publication date: 2021-07-01
Anticipated expiration: 2038-03-16
Also published as: AU2018241298A1; JP2020515549A; EP3604263A4; CN110461805A; WO2018178439A1; ES2686136B1; US10597342B2; EP3604263A1; JP7066737B2; US20200010391A1; ES2686136A1; EP3604263B1

Abstract

The invention relates to a method for the synthesis of 9,10-Bis(chloromethyl)anthracene, comprising the mixing of the reagents, anthracene and 1,3,5-Trioxane, a phase transfer catalyst selected from the group comprising quarternary ammonium salt and crown ether with hydrochloric acid and acetic acid.

Description

P1645AUPC

1

METHOD FOR THE SYNTHESIS OF 9,10 BIS(CHLOROMETHYL)ANTHRACENE

FIELD OF THE INVENTION

The present invention relates to a method for the synthesis of 9,10 bis(chloromethyl)anthracene. Disclosed is a method involving the mixing of anthracene, 1,3,5-trioxane, the catalyst hexadecyltrimethylammonium bromide, hydrochloric acid and acetic acid. 9,10-bis(chloromethyl)anthracene is a compound used in specific recognition, electronic molecular machines, drug carriers and catalysts in organic synthesis, optical fluorescence, photodynamic therapy and optical data storage, microfabrication, precursor in the preparation of anthracene meso bi-substituted derivatives.

BACKGROUND OF THE INVENTION

The compound 9,10-bis(chloromethyl)anthracene

Ci

Cl

is a compound of high interest as an intermediate for chemical synthesis processes where the inclusion of an anthracene skeleton that is doubly substituted in the meso or benzylic position (CH2 adjacent to the aromatic ring) is necessary.

Document J. Am. Chem. Soc. 1955, 77, 2845-2848 describes a chloromethylation method of anthracene as a versatile intermediate in obtaining other derivatives by means of displacement reactions, that is, from 9,10 bis(chloromethyl)anthracene to a wide range of available functionalisation. In summary, the synthetic method described in this document consists of passing a current of cool hydrogen chloride, continuously generated in situ, to a mixture of 1,4 dioxane, anthracene, p-formaldehyde and fuming hydrochloric acid. The crude reaction product is heated under reflux, maintaining the current of hydrogen chloride for several hours, after the interruption thereof, the reflux system continues for another 24 hours. After filtering and thorough washing to remove impurities, the compound is finally obtained in solid form with a fairly moderate yield of 67%. As can be seen, it is a rather laborious experiment with a yield that can be significantly improved. Other synthetic methods have been described in the state of the art, such as that described in RSC Adv. 2015, 5, 73951-73957, where the synthesis is carried out in the presence of an organic solvent (dioxane) and at high temperatures (100 0C). However, the inventors of the present application have found serious reproducibility problems in this method. When the inventors reproduced the method, they found that 9,10-bis(chloromethyl)anthracene is not obtained, as stated in the scientific article, despite having repeated this reaction several times, and being unsuccessful every time. Therefore, this synthesis route must be discarded. 9,10-bis(chloromethyl)anthracene can be acquired from different suppliers. On their website, Sigma-Aldrich classifies this product within a selection of "uncommon and unique chemical reagents", thus justifying its fairly high price. However, this compound is widely used in scientific work as a structural intermediate for anthracene, which is freely chemically derivatised, mainly seeking the occurrence of colorimetric and fluorescent optical properties. Some applications of this compound have been published in the state of the art. Document RSC Adv. 2015, 5, 73951-73957 describes this compound as a new photoactive cyclophanes skeleton with molecular rigidity for use in specific recognition, electronic molecular machines, drug carriers and catalysts in organic synthesis. Document Chem. Mater. 2004, 16, 2783-2789 describes this compound as organic matter for application in optical fluorescence, photodynamic therapy and optical data storage and microfabrication through donor-bridge-acceptor compounds or donor-bridge-donor compounds. This compound acts as a valuable precursor in the preparation of anthracene meso bi-substituted derivatives in positions 9 and 10, such as amines and the respective hydrochlorides thereof, amides, isocyanates, alcohols, esters, ethers, thiols, nitriles, acids and phosphonates.

P1645AUPC

3

It is not admitted that any of the information in this patent specification is common general knowledge, or that the person skilled in the art could be reasonably expected to ascertain or understand it, regard it as relevant or combine it in any way before the priority date.

DESCRIPTION OF THE INVENTION

The invention aims to provide a method for the synthesis of 9,10 bis(chloromethyl)anthracene with a higher yield to that obtained with the methods of the state of the art, or at least to provide a useful alternative for those concerned with the synthesis of 9,10-bis(chloromethyl)anthracene.

It is also desirable to provide for simpler scaling and to meet the green chemistry principles, e.g. by using a catalytic method and an aqueous reaction medium without the presence of organic solvents.

In a first aspect, the present invention provides a method for the synthesis of 9,10-bis(chloromethyl)anthracene, comprising the mixing of the reagents, anthracene and 1,3,5-trioxane, a phase transfer catalyst selected from the group comprising quarternary ammonium salt and crown ether with hydrochloric acid and acetic acid.

In the present specification, a phase transfer catalyst is the chemical species that makes possible and catalyses chemical reactions between two or more reagents situated in two or more phases, such that it enables a reactivity that, without the phase transfer catalyst, would not be possible. The mode of operation is based on the arrangement of the catalyst between the phases, enabling the physicochemical connection between the reagents that actively participate in the reaction.

In the present specification, the term 'comprises' and its grammatical variants has a meaning that is determined by the context in which it appears. Accordingly, the term should not be interpreted exhaustively unless the context dictates so.

Another embodiment is the method according to the first aspect of the invention, wherein the concentration of the phase transfer catalyst is between 1 and 5 mol%.

P1645AUPC

3A Another embodiment is the method according to the first aspect of the invention, wherein the concentration of hexadecyltrimethylammonium bromide is between 2 and 4 mol%.

Another embodiment is the method according to the first aspect of the invention, wherein the concentration of hexadecyltrimethylammonium bromide is between 2 and 3 mol%.

Another embodiment is the method according to the first aspect of the invention, wherein the molar ratio of 1,3,5-trioxane:anthracene is between 0.5 and 3.

Another embodiment is the method according to the first aspect of the invention, wherein the molar ratio of 1,3,5-trioxane:anthracene is between 1 and 2.

Another embodiment is the method according to the first aspect of the invention, comprising the following additional stages: (c) filtering the mixture resulting from stage (b), (d) washing with water and (d) washing with ethanol. The method according to the first aspect of the invention can be carried out at room temperature or heated to temperatures higher than room temperature. The 9,10-bis(chloromethyl)anthracene compound appears very quickly, within a few minutes. This compound is present in less than 10 minutes from the start of the method according to the first aspect of the invention. The method according to the first aspect of the invention has a series of advantages with respect to the methods described in the state of the art, which are: - the absence of any organic solvent in the synthesis process, the medium used being exclusively aqueous, which entails preventing the need to treat the organic solvents; - the absence of accessory gas supply currents to the process; - the high reaction yield measured as the mass of the final purified product in solid state; - not requiring high temperatures in the synthesis, since it is not necessary to reflux the solvent; - not requiring further purification of the final product by crystallisation has had been the case; - the excellent reproducibility of the method.

BRIEF DESCRIPTION OF THE FIGURES Figure 1. 400 MHz proton NMR spectrum in deuterated chloroform and at room temperature of 9,10-bis(chloromethyl)anthracene.

DESCRIPTION OF EMBODIMENTS

Reagents used The reagents used in the method for the synthesis were used based on the commercial compound without purification or enrichment thereof before the synthesis. The reagents anthracene (Anthracene ReagentPlus@, 99%, commercial code 141062-25G, 56.00 €, Spain), acetic acid (Acetic acid ReagentPlus@, 99%, commercial code A-6283-1L, 43.60 €, Spain) and 1,3,5-trioxane (1,3,5 trioxane, 99%, commercial code T81108-100G, 23.30 €, Spain) were acquired from Sigma-Aldrich. The hydrochloric acid (Hydrochloric acid reagent grade, 37%, 1 L, 28.23 €) was supplied by Scharlab. Lastly, the hexadecyltrimethylammonium bromide(Hexadecyltrimethylammonium bromide, 96%, commercial code 52370-100G, 32.00 €, Spain) is from Fluka.

oo~oBr AOH 0 14 HCI aq

Anthracene Acetic acid 1,3,5-trioxane Hexadecyltrimethylammonium Hydrochloric acid bromide

Method for the synthesis of 9,10-bis(chloromethyl)anthracene In general, the experimental method can be described as follows: the solid reagents (anthracene, 1,3,5-trioxane and hexadecyltrimethylammonium bromide as a catalyst) are placed in a round flask without an established order of priority. Firstly, the hydrochloric acid is added to the mixture, then the acetic acid, all at room temperature and under constant and vigorous stirring (1500 rpm). Then, the mixture is exposed to different temperatures in order for the reaction to take place during a specific period of time, wherein the medium becomes a yellow colour and has a powdery appearance, without dissolving the solid present. After a fixed reaction time, the content of the flask is filtered in order to collect the yellow precipitate and it is thoroughly washed with water to eliminate the remains of trioxane, catalyst and acid species present in the medium. As a final step, the obtained solid is washed with ethanol to remove the remains of water from the washing and it is left to stove dry at 70 C for 2 hours until completely dry.

Several reaction protocols have been tested with different values for reaction temperature, time and excess of 1,3,5-trioxane as a source of formaldehyde with respect to the limiting amount of anthracene. Examples 1-4 describe the different methods for the synthesis of 9,10 bis(chloromethyl)anthracene that were tested.

Example 1. Method for the synthesis of 9,10-bis(chloromethyl)anthracene

CI 1,3,5-trioxane (2 eq) Hexadecyltrimethylammonium bromide (2.5 mol%)

conc. HCI + conc. AcOH 24 h, 1000C CI

Description of reagent amounts used: Anthracene -> 500 mg, 2.8 mmol. 1,3,5-trioxane -> 504 mg, 2 eq (5.6 mmol). Hexadecyltrimethylammonium bromide -> 25 mg, 0.07 mmol (2.5 mol%) Hydrochloric acid 37% -> 10 ml Acetic acid 99% -> 2.5 ml Reaction yield: 89%

Example 2. Method for the synthesis of 9,10-bis(chloromethyl)anthracene CI 1,3,5-trioxane (2 eq) Hexadecyltrimethylammonium bromide (2.5 mol%)

conc. HCI+ conc. AcOH 24 h, 600C CI Description of reagent amounts used: Anthracene -> 500 mg, 2.8 mmol. 1,3,5-trioxane -> 504 mg, 2 eq (5.6 mmol). Molar ratio 1,3,5-trioxane:anthracene: 2 Hexadecyltrimethylammonium bromide -> 25 mg, 0.07 mmol (2.5 mol%) Hydrochloric acid 37% -> 10 ml Acetic acid 99% -> 2.5 ml Reaction yield: 96%.

Example 3. Method for the synthesis of 9,10-bis(chloromethyl)anthracene

CI 1,3,5-trioxane (2 eq) Hexadecyltrimethylammonium bromide (2.5 mol%)

C M -~ conc. HCI+ conc. AcOH 14 h, 600C CI Description of reagent amounts used: Anthracene -> 500 mg, 2.8 mmol. 1,3,5-trioxane -> 504 mg, 2 eq (5.6 mmol). Molar ratio 1,3,5-trioxane:anthracene: 2 Hexadecyltrimethylammonium bromide -> 25 mg, 0.07 mmol (2.5 mol%) Hydrochloric acid 37% -> 10 ml Acetic acid 99% -> 2.5 ml Reaction yield: 93%.

Example 4. Method for the synthesis of 9,10-bis(chloromethyl)anthracene CI 1,3,5-trioxane (1 eq) Hexadecyltrimethylammonium bromide (2.5 mol%)

conc. HCI+ conc. AcOH 24 h, 60 °C CI Description of reagent amounts used: Anthracene -> 500 mg, 2.8 mmol. 1,3,5-trioxane -> 504 mg, 1 eq (2.8 mmol). Molar ratio 1,3,5-trioxane:anthracene: 1 Hexadecyltrimethylammonium bromide -> 25 mg, 0.07 mmol (2.5 mol%) Hydrochloric acid 37% -> 10 ml Acetic acid 99% -> 2.5 ml Reaction yield: 97% of solid that does not correspond through NMR analysis with pure product, but rather there is presence of unreacted anthracene. Below, Table 1 shows an informative table summarising the above results based on the variables.

Table 1

Example Example Example Example Example Variables 1 2 3 4 5 Time (h) 24 24 14 24 24 Temperature 100 60 60 60 25 (°C) Molar ratio 1,3,5- 2 trioxane:anthracene Yield by weight (%) 89 96 93 97 74

The 9,10-bis(chloromethyl)anthracene synthesised in Examples 1-4 was characterised through proton nuclear magnetic resonance (NMR) experiments in a Bruker 400 MHz NMR, carrying out the measurements at room temperature and using deuterated chloroform (CDCI 3) as a solvent in the analysis. Figure 1 shows the 400 MHz proton NMR spectrum in deuterated chloroform and at room temperature. This spectrum is identical for the compound obtained in Examples 1-4. The spectrum coincides with the spectrum described in the state of the art 5( H4 0 0 MHz, CDC 3: 5.77 ppm, singlet, 4H; 7.74-7.77 ppm, multiplet, 4H; 8.53-8.55 ppm, multiplet, 4H).

Example 5. Method for the synthesis of 9,10-bis(chloromethyl)anthracene

CI 1,3,5-trioxane (2 eq) Hexadecyltrimethylammonium bromide (2.5 mol%)

m- -conc. HCI + conc. AcOH 24 h, 250C CI Description of reagent amounts used: Anthracene -> 500 mg, 2.8 mmol. 1,3,5-trioxane -> 504 mg, 2 eq (5.6 mmol). Molar ratio 1,3,5-trioxane:anthracene: 2 Hexadecyltrimethylammonium bromide -> 25 mg, 0.07 mmol (2.5 mol%) Hydrochloric acid 37% -> 10 ml Acetic acid 99% -> 2.5 ml Reaction yield: 74% of solid.

Example 6. Method for the synthesis of 9,10-bis(chloromethyl)anthracene In this example, the following phase transfer catalysts were used: Tetrabutylammonium bromide Tetrabutylammonium fluoride Tetrabutylammonium nitrate Tetrabutylammonium hexafluorophosphate Tetrabutylammonium perchlorate Benzyl trimethylammonium chloride 4-carboxybenzyl-18-crown-6 (1,4,7,10,13,16-Hexaoxacyclooctadecane 1,4,7,10,13,16-Hexaoxacyclooctadecane) crown ether 18-crown-6 (carboxylic acid 18-2,3,5,6,8,9,11,12,14,15 decahydrobenzo[b][1,4,7,10,13,16]hexaoxacyclooctadecane 2,3,5,6,8,9,11,12,14,15 decahydrobenzo[b][1,4,7,10,13,16]hexaoxacyclooctadecane-18-carboxylic acid) crown ether Table 2 shows the reaction parameters and yield obtained in the experiments of this example: Table 2

Phase transfer catalyst Reaction time (h) / Yield by weight of pure used temperature (0C) product(%) Tetrabutylammonium 24/60 83 bromide Tetrabutylammonium 24/60 80 fluoride Tetrabutylammonium 24/60 71 nitrate Tetrabutylammonium 24/60 70 hexafluorophosphate Tetrabutylammonium 24/60 75 perchlorate Benzyl 24/60 70 trimethylammonium chloride

Phase transfer catalyst Reaction time (h) / Yield by weight of pure used temperature (0C) product(%) 4-carboxybenzyl-18- 24/60 67 crown-6 crown ether 18-crown-6 crown ether 24 / 60 63

Claims

1. A method for the synthesis of 9,10-bis(chloromethyl)anthracene, comprising the mixing of the reagents, anthracene and 1,3,5-trioxane, a phase transfer catalyst selected from the group comprising quarternary ammonium salt and crown ether with hydrochloric acid and acetic acid.

2. The method according to claim 1, characterised in that the concentration of the phase transfer catalyst is between 1 and 5 mol%.

3. The method according to claim 1 or 2, characterised in that the molar ratio of 1,3,5-trioxane: anthracene is between 0.5 and 3.

EDITORIAL NOTE

2018241298

- The page numbering is a continuation of the specification numbering